Use of metalloprotease inhibitors to induce and/or stimulate the growth of head hair or other hairs and/or to slow down their loss

ABSTRACT

A method for inducing and/or stimulating the growth of hair and/or slowing down hair loss comprising administering an effective amount of at least one metalloprotease inhibitor or any functional biological equivalent thereof and an acceptable carrier therefor.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of copending U.S. patentapplication Ser. No. 09/700,195, filed Feb. 20, 2001, now allowed,incorporated by reference herein in its entirety and relied upon, whichis the U.S. national phase of International Application No.PCT/FR99/01124, filed May 11, 1999, published as WO99/58101 on Nov. 18,1999, and claiming the priority of application Ser. No. 98/05,968, filedMay 12, 1998 in France.

[0002] The present invention relates to the use, in or for thepreparation of a composition, as active principle in a physiologicallyacceptable medium, of an effective amount of at least onemetalloprotease inhibitor, or of any functional biological equivalent,which is intended to induce and/or stimulate the growth of head hair orother hairs and/or to slow down their loss.

[0003] In humans, the growth and renewal of the hair are mainlydetermined by the activity of the hair follicles and by theirdermo-epidermal environment. Their activity is cyclic and essentiallycomprises three phases, i.e. the anagenic phase, the catagenic phase andthe telogenic phase.

[0004] The active anagenic phase or growth phase, which lasts forseveral years and during which the hair gets longer, is followed by avery short and transient catagenic phase which lasts a few weeks, andthen comes a rest phase, known as the telogenic phase, which lasts a fewmonths.

[0005] At the end of the rest period, the hair falls out and anothercycle begins. The head of hair is thus under constant renewal, and outof the approximately 150,000 hairs which make up a head of hair, at anygiven moment, approximately 10% of them are at rest and will thus bereplaced within a few months.

[0006] In a large number of cases, early hair loss occurs in individualswho are genetically predisposed, and it usually affects men. This moreparticularly concerns androgenetic or androgenic or evenandrogenogenetic alopecia.

[0007] This alopecia is essentially due to a disruption in hair renewalwhich leads, in a first stage, to an acceleration of the frequency ofthe cycles, at the expense of the quality of the hair and then at theexpense of its quantity. A gradual depletion of the head of hair takesplace by regression of the so-called “terminal” hairs at the downystage. Regions are preferentially affected, in particular the temples orfrontal bulbs and the back of the head in men, while in women diffusealopecia of the vertex is observed.

[0008] Substances for suppressing or reducing alopecia, and inparticular for inducing or stimulating hair growth or reducing hairloss, have been sought for many years in the cosmetics andpharmaceutical industries.

[0009] Admittedly, in this respect, a large number of very diverseactive compounds have already been proposed, such as, for example,2,4-diamino-6-piperidinopyrimidine 3-oxide or “Minoxidil” described inU.S. Pat. No. 4,596,812, or the many derivatives thereof, such as thosedescribed, for example, in patent applications EP 0 353 123, EP 0 356271, EP 0 408 442, EP 0 522 964, EP 0 420 707, EP 0 459 890 and EP 0 519819. Mention may also be made of6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine and itsderivatives, which are described more particularly in patent U.S. Pat.No. 4,139,619.

[0010] However, it would generally still be advantageous and useful tobe able to provide active compounds other than those already known.

[0011] Now, after considerable research conducted in this matter, theApplicant has just discovered that a metalloprotease inhibitor, or anyfunctional biological equivalent, makes it possible to induce and/orstimulate the growth of head hair or other hairs, and/or to reduce theirloss in an effective manner.

[0012] Metalloproteases (MMPs) are members of a family of proteoliticenzymes (endoproteases) which contain a zinc atom co-ordinated to 3cysteine residues and one methionine residue in their active site andwhich degrade the macromolecular components of the extracellular matrixand the basal sheets at neutral pH (collagen, elastin, etc.). Theseenzymes, which are very widely distributed in the living world, arepresent, but weakly expressed, in normal physiological situations suchas organ growth and tissue renewal. However, their overexpression in manand their activation are associated with many processes which involvethe destruction and remodelling of the matrix. This entails, forexample, an uncontrolled resorption of the extracellular matrix.

[0013] Metalloproteases are produced and secreted in an inactivezymogenic form (pro-enzyme). These zymogenic forms are then activated inthe extracellular environment by the removal of a propeptide region. Themembers of this family can activate each other.

[0014] Regulation of the activity of MMPs thus takes place at the levelof the expression of the genes (transcription and translation), at thelevel of the activation of the zymogenic form, or at the level of thelocal control of the active forms.

[0015] The main regulators of the activity of MMPs are the tissueinhibitors of metalloproteases, or TIMPs. However, the expression ofMMPs is also modulated by growth factors, cytokines, oncogenic products(ras, jun) or matrix constituents.

[0016] The metalloprotease family consists of several well-definedgroups based on their resemblances in terms of substrate specificity andstructure (see Woessner J. F., Faseb Journal, vol. 5, 1991, 2145). Amongthese groups, mention may be made of collagenases intended to degradefibrillar collagens (MMP-1 or interstitial collagenase, MMP-8 orneutrophil collagenase, and MMP-13 or collagenase 3), gelatinases whichdegrade type IV collagen or any form of denatured collagen (MMP-2 orgelatinase A (72 kDa), MMP-9 or gelatinase B (92 kDa)), stromelysinswhose broad spectrum of activity applies to extracellular matrixproteins such as glycoproteins (fibronectin, laminin), proteoglycans,etc. or alternatively membrane metalloproteases.

[0017] The Applicant has now discovered that metalloproteases arepresent in the internal structures of hair follicles, namely in theinner epithelial sheath (IRS). In particular, MMP-9 is found in the IRS.

[0018] Now, it is known that in the course of the hair cycle, hairfollicles pass from a low-level location in the dermis in the anagenicphase, to a high-level location in the dermis during the telogenicphase. This movement should be accompanied by a change in theextracellular matrix which allows the migration of the follicle, thischange possibly being due to an expression of the MMPs, bringing about acontrolled degradation of the said extracellular matrix. It is at theend of the telogenic phase that hair loss occurs. However, it is alsoknown that cytokines and growth factors have an influence on the haircycle. For example, epidermal growth factor (EGF) promotes the in vitrotransition from the anagenic phase to the catagenic phase (formation ofa “club” structure characteristic of the catagenic phase), this beingthe phase which precedes the loss of the head hairs or other hairs. Itis also known, as the Applicant has demonstrated, that there is aninflammatory phase in alopecia.

[0019] The Applicant has shown that the MMPs and particularly MMP-9, canbe induced by interleukin-1 and/or EGF, in particular in the fibroblastsof the dermal papillae.

[0020] The advantage of reducing the expression of MMPs in the scalp inorder to slow down or inhibit the degradation of the perifollicularmatrix and thus to slow down or even prevent hair loss may thus beappreciated.

[0021] The Applicant thus proposes the use of metalloprotease inhibitorsto induce and/or stimulate the growth of head hair or other hairs and/orto slow down their loss.

[0022] Thus, the invention relates to the use, in or for the preparationof a composition, of an effective amount of at least one metalloproteaseinhibitor or of any functional biological equivalent, which is intendedto induce and/or stimulate the growth of head hair or other hairs and/orto slow down their loss.

[0023] The expression “functional biological equivalent” means anymolecule which is functionally equivalent in terms of biologicalfunction, at least one of the components of which may have been changedfor an equivalent component.

[0024] Examples which may be mentioned are peptides, one biologicalequivalent of which may be a peptide in which at least one amino acidresidue has been replaced with another amino acid having a similarhydropathic index.

[0025] The expression “metalloprotease inhibitor” means any moleculecapable of regulating the activity of MMPs either at the level of theexpression of the genes (transcription and translation) or at the levelof the activation of the zymogenic form of MMPs, or alternatively at thelevel of the local control of the active forms.

[0026] The main regulators of the activity of MMPs are natural moleculespresent in the tissues, known as tissue inhibitors of metalloproteases,or TIMPs.

[0027] However, these inhibitors may also be known chemical moleculessuch as, for example, hydroxamic acid derivatives, cation-chelatingagents, growth factors, cytokines, oncogenic products (ras, jun) ormatrix constituents.

[0028] According to the invention, tissue inhibitors of metalloproteases(TIMPs) such as, for example, the peptides known in the prior art underthe names TIMP-1, TIMP-2, TIMP-3 and TIMP-4 (Woessner J. F., FasebJournal, 1991) are preferably used.

[0029] Thus, the invention relates more particularly to the use, in orfor the preparation of a composition, of an effective amount of at leastone tissue inhibitor of metalloproteases (TIMP) or of any functionalbiological equivalent, the inhibitor or the composition being intendedto induce and/or stimulate the growth of head hair or other hairs and/orto slow down their loss.

[0030] The peptides known in the prior art under the names TIMP-1,TIMP-2, TIMP-3 and TIMP-4 are preferably used according to the inventionas tissue inhibitors of metalloproteases.

[0031] Needless to say, according to the invention, the metalloproteaseinhibitors can be used alone or as a mixture.

[0032] It may be the case that, for reasons of resistance todegradation, it is necessary according to the invention to use aprotected form of the metalloprotease inhibitor. The form of theprotection should obviously be a biologically compatible form. Manybiologically compatible forms of protection may be envisaged, such as,for example, acylation or acetylation of the amino-terminal end oramidation of the carboxy-terminal end.

[0033] Thus, the invention relates to a use as defined above,characterized in that the metalloprotease inhibitor is in a protected orunprotected form.

[0034] A protection based either on the acylation or acetylation of theamino-terminal end, or on the amidation of the carboxy-terminal end, oralternatively on both approaches, is preferably used according to theinvention.

[0035] Among the chemical inhibitors which may be mentioned are thiolsand hydroxamates.

[0036] The amount of metalloprotease inhibitor which can be usedaccording to the invention obviously depends on the desired effect andshould be in an amount which is effective to induce and/or stimulate thegrowth of head hair or other hairs and/or to slow down their loss.

[0037] By way of example, the amount of metalloprotease inhibitor whichcan be used according to the invention may range, for example from 0.01%to 5% and preferably from 0.05% to 2% relative to the total weight ofthe composition.

[0038] The composition is preferably a cosmetic composition.

[0039] The composition according to the invention can be administeredenterally or parenterally. Preferably, via the parenteral route, thecomposition is administered topically.

[0040] The physiologically acceptable medium in which the peptide isused according to the invention may be anhydrous or aqueous. Theexpression “anhydrous medium” means a solvent medium containing lessthan 1% water. This medium may consist of a solvent or a mixture ofsolvents chosen more particularly from C₂-C₄ lower alcohols such asethyl alcohol, alkylene glycols such as propylene glycol, and alkyleneglycol alkyl ethers or dialkylene glycol alkyl ethers, the alkyl oralkylene radicals of which contain from 1 to 4 carbon atoms. Theexpression “aqueous medium” means a medium consisting of water or of amixture of water and another physiologically acceptable solvent, chosenin particular from the organic solvents mentioned above. In this lastcase, when these other solvents are present, they representapproximately 5% to 95% by weight of the composition.

[0041] It is possible for the physiologically acceptable medium tocontain other adjuvants usually used in cosmetics, such as surfactants,thickeners or gelling agents, cosmetic agents, preserving agents, andacidifying and basifying agents that are well known in the prior art,and in amounts that are sufficient to obtain the desired presentationform, in particular a more or less thickened lotion, a gel, an emulsionor a cream. The composition can optionally be used in a form pressurizedas an aerosol or vaporized from a pump-dispenser bottle.

[0042] It is also possible for the peptide to be used in combinationwith compounds for further improving the activity on hair regrowthand/or on slowing down hair loss, which have already been described forthis activity.

[0043] Among the latter compounds, mention may be made moreparticularly, in a non-limiting manner, of:

[0044] nicotinic acid esters, in particular including tocopherylnicotinate, benzyl nicotinate and C₁-C₆ alkyl nicotinates such as methylor hexyl nicotinate;

[0045] pyrimidine derivatives, such as6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine also knownas “Minoxidil” and as described in U.S. Pat. No. 4,139,619;

[0046] antiandrogenic agents

[0047] 5- -reductase inhibitors;

[0048] OH-radical scavengers, such as dimethylsulfoxide;

[0049] peptides such as, for example, the tripeptide Lys-Pro-Val;

[0050] microorganism extracts, particularly bacterial extracts;

[0051] plant extracts.

[0052] Other compounds can also be added to the above list, namely, forexample, phospholipids such as lecithin, linoleic acid, linolenic acid,salicylic acid and derivatives thereof described in French patent FR 2581 542, for instance salicylic acid derivatives bearing an alkylradical containing from 2 to 12 carbon atoms in position 5 of thebenzene ring, hydroxycarboxylic or ketocarboxylic acids and estersthereof, lactones and the corresponding salts thereof, carotenoids,eicosatetraenoic and eicosatrienoic acids or esters and amides thereof,vitamin D and derivatives thereof.

[0053] The cosmetic composition according to the invention can beapplied to the alopecic regions of the scalp and hair of an individual,and is optionally left in contact for several hours and is optionally tobe rinsed out. For example, the cosmetic composition containing aneffective amount of at least one metalloprotease inhibitor can beapplied to the hair and the scalp in the evening, kept in contactthroughout the night and optionally shampooed out in the morning. Theseapplications can be repeated daily for one or more months depending onthe individual.

[0054] Thus, a subject of the present invention is also a cosmeticprocess for treating the hair and/or the scalp, characterized in that itconsists in applying a cosmetic composition containing an effectiveamount of at least one metalloprotease inhibitor to the hair and/or thescalp, in leaving this composition in contact with the hair and/or thescalp, and optionally in rinsing it off.

[0055] The treatment process has the characteristics of a cosmeticprocess since it improves the aesthetics of the hair by making it morevigorous and making it look better.

[0056] Examples will now be given by way of illustration, which shouldnot in any way limit the scope of the invention.

EXAMPLE I

[0057] An example of a daily lotion is as follows: TIMP-1 0.01 g TIMP-20.01 g 2,4 Diaminopyrimidine 3-oxide 0.75 g 95° ethanol 30 g Fragranceqs Dyes qs Demineralized water qs 100 g

EXAMPLE 2

[0058] An example of a liposomal gel is as follows: Natipide II¹ (i.e. 2g of phospholipids) 10 g TIMP-2 0.025 g Carbomer 0.25 g Triethanolamineqs pH = 7 Preserving agents qs Demineralized water qs 100 g

What is claimed is:
 1. A method for inducing and/or stimulating thegrowth of hair and/or slowing hair loss comprising applying to the hairand/or the scalp of an individual in need thereof, a topical compositioncomprising an effective amount of at least one metalloprotease inhibitorother than chelating calcium ions and growth factors, in aphysiologically acceptable medium.
 2. A method for inducing and/orstimulating the growth of hair and/or slowing hair loss comprisingapplying to the hair and/or the scalp of an individual in need thereof,a topical composition comprising an effective amount of at least onemetalloprotease inhibitor selected from the group consisting of tissueinhibitors, cytokines, oncogenic products, matrix inhibitors, andchemical inhibitors other than chelating calcium ions, in aphysiologically acceptable medium.
 3. A method according to claim 2,wherein the metalloprotease inhibitor is a chemical inhibitor or atissue inhibitor of metalloproteases.
 4. A method for inducing and/orstimulating the growth of hair and/or slowing hair loss comprisingapplying to the hair and/or the scalp of an individual in need thereof,a topical composition comprising at least one chemical inhibitor ofmetalloproteases other than chelating calcium ions, and aphysiologically acceptable medium.
 5. A method according to claim 4,wherein the chemical inhibitor is a thiol or a hydroxamate.
 6. Themethod according to claim 1, wherein said at least one inhibitor ispresent in an amount of between 0.01% and 5% relative to the totalweight of the composition.
 7. The method according to claim 2, whereinsaid at least one inhibitor is present in an amount of between 0.01% and5% relative to the total weight of the composition.
 8. The methodaccording to claim 3, wherein said at least one inhibitor is present inan amount of between 0.01% and 5% relative to the total weight of thecomposition.
 9. The method according to claim 4, wherein said at leastone inhibitor is present in an amount of between 0.01% and 5% relativeto the total weight of the composition.
 10. The method according toclaim 5, wherein said at least one inhibitor is present in an amount ofbetween 0.01% and 5% relative to the total weight of the composition.11. The method according to claim 1, wherein said at least one inhibitoris present in an amount of between 0.05% and 2% relative to the totalweight of the composition.
 12. The method according to claim 2, whereinsaid at least one inhibitor is present in an amount of between 0.05% and2% relative to the total weight of the composition.
 13. The methodaccording to claim 3, wherein said at least one inhibitor is present inan amount of between 0.05% and 2% relative to the total weight of thecomposition.
 14. The method according to claim 4, wherein said at leastone inhibitor is present in an amount of between 0.05% and 2% relativeto the total weight of the composition.
 15. The method according toclaim 5, wherein said at least one inhibitor is present in an amount ofbetween 0.05% and 2% relative to the total weight of the composition.16. The method according to claim 1, further comprising leaving saidcomposition in contact with the hair and/or the scalp for a sufficienttime and optionally rinsing said composition from the treated area. 17.The method according to claim 2, further comprising leaving saidcomposition in contact with the hair and/or the scalp for a sufficienttime and optionally rinsing said composition from the treated area. 18.The method according to claim 3, further comprising leaving saidcomposition in contact with the hair and/or the scalp for a sufficienttime and optionally rinsing said composition from the treated area. 19.The method according to claim 4, further comprising leaving saidcomposition in contact with the hair and/or the scalp for a sufficienttime and optionally rinsing said composition from the treated area. 20.The method according to claim 5, further comprising leaving saidcomposition in contact with the hair and/or the scalp for a sufficienttime and optionally rinsing said composition from the treated area.